Because lyophilization dries a product from the frozen state under temperature controlled conditions, the refrigeration system's process capabilities and performance are critical to a successful commercial lyophilization operation. Part 1 of this article outlines recent trends in pharmaceutical manufacturing and their impact on the evolution of refrigeration technology in lyophilization. It also explains the advantages and disadvantages of choosing a refrigeration system that uses liquid nitrogen instead of mechanical compressors, and its affect on the overall operation. Part 2 of this article, to be published in the December 2007 issue of BioPharm International, will detail design and performance considerations for cryogenic nitrogen refrigeration in a freeze-dryer. The relative cost affect of choosing a cryogenic versus a mechanical refrigeration system will also be discussed as related to the lyophilization process.

Lyophilization (freeze-drying) is increasingly used to gently stabilize pharmaceutical and biopharmaceutical products, and intermediates.1-4 Its recent growth is being driven by the escalating global demand for aseptic packaging and preservation of parenteral drugs, as well as by the rise in the production of biologics, including protein-based therapeutics and vaccines.2-4 According to industry experts, the corresponding increase in lyophilization capacity has been fueling double-digit growth in global cGMP freeze-drying equipment sales, which have reached approximately $250 million per year. The global installed base is estimated to be in excess of 3,000 cGMP production units.

During lyophilization, most of the solvent (e.g., water or alcohol) is removed from a product after it is frozen and placed under vacuum. The process actually consists of three separate, but interdependent steps: 1) freezing, 2) primary drying (ice sublimation), and 3) secondary drying (moisture desorption). During primary drying, more than 90% of the solvent changes directly from solid to vapor phase through sublimation. The residual solvent remains adsorbed on the product as moisture. Some of this remaining solvent is desorbed during secondary drying to attain a moisture level too low to permit biological growth or chemical reactions, while still preserving the activity and integrity of the freeze-dried product.3-5

Key advantages driving the growth of lyophilization as a preferred fill-and-finish step include the enhanced stability of freeze-dried powder, the ability to remove solvent with minimal heating and concentration effects, the relative ease of aseptically processing a liquid in a freeze-dryer, and rapid and easy dissolution of the product upon reconstitution. All these advantages facilitate minimizing the time to market of a novel therapeutic agent, establishing an early marketing lead, and collecting increased revenues. Disadvantages of this method include increased handling and processing time, the need for a sterile diluent upon reconstitution, and the cost and complexity of related equipment, including its operation and maintenance.1,3,5,6

REFRIGERATION TRENDS IN FREEZE-DRYERS

Key Components of a Lyophilizer

During lyophilization, the product is first frozen, then dried from this frozen state under precise temperature- and pressure-controlled conditions. The refrigeration system's process capabilities, flexibility, reliability, and performance are all critical to a successful commercial lyophilization operation. Historically, most freeze-dryers have used mechanical refrigeration. Even though approximately 80% of lyophilizer service problems arise in the mechanical refrigeration system,7 these compressor-based units have accounted for 90–95% of freeze-dryer installations.

However, since the early 1990s, cryogenically refrigerated freeze-dryers have been claiming an increasing market share.7–11
These reliable, flexible, and well-proven systems use liquid nitrogen (LN2) or cold gaseous nitrogen (GN2) to cool the components of the freeze-dryer.

In recent years, both the efficiency and flexibility of cryogenic refrigeration systems for freeze-drying have further increased, and their cost of ownership has decreased.8–11 With these improvements, LN2/GN2 systems are ready for mainstream processes. In this article and the subsequent cryogenic lyophilization article, we outline key considerations to help users make informed decisions about what type of refrigeration is best for a particular lyophilization situation.